Although not mutagenic by Ames test, 2,5-dimethylfuran (DMF), a leading biofuel candidate, was found to induce chromosomal damage in cultured murine cells, suggesting that it may be genotoxic. We sought to prioritize the environmental and biological impacts of using DMF as a combustible biofuel. First, we assessed DMF and its combustion intermediates for potential persistence, bioaccumulation, and aquatic toxicity (PBT) using PBT profiler. Our findings predict DMF to have moderate-level aquatic toxicity; however, a greater subset of the combustion intermediates is predicted to have moderate- and high-level aquatic toxicity with bioaccumulation and persistence concerns. Second, we assessed the biological impact of DMF by testing for statistically significant chemical–disease associations. No direct associations for DMF were found; however, indirect associations were identified from two structurally similar analogs. Curated associations between furfuryl alcohol to kidney neoplasm and adenoma, and significant inferred associations between furan to lung neoplasm, drug-induced liver injury, and experimentally induced liver cirrhosis were found, based on 21 furan–gene interactions. Nine of 49 DMF combustion intermediates analyzed, including benzene and 1,3-butadiene, were found to have associations with 26 tumors and systemic diseases. Although inadequate for a stand-alone risk assessment, our data suggest that DMF combustion intermediates pose a much broader range of hazards than DMF itself, and that both should be further investigated. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.